Overview of genetic causes for epilepsy in children
LISA T. EMRICK MD MEDICAL DIRECTOR, NEUROGENETICS ASSISTANT PROFESSOR DIVISION OF NEUROLOGY AND DEVELOPMENTAL NEUROSCIENCE BAYLOR COLLEGE OF MEDICINE AND TEXAS CHILDREN’S HOSPITAL HOUSTON, TX Disclosures
Employee of Baylor College of Medicine (BCM). Baylor Genetics Laboratories derives revenue from genetic testing, including metabolomic analyses, whole exome and genome sequencing Consultant for PTC Therapeutics regarding AADC deficiency PI for Phase II/III Clinical Trial - Lysogene Objectives
Describe the different types of seizures and epilepsy Describe the broad genetic causes of epilepsy in children Understand the concept of precision medicine for the treatment of epilepsy Epilepsy – historical context What is epilepsy?
International League Against Epilepsy (ILAE) https://www.ilae.org/guidelines/definition-and-classification/definition-of-epilepsy-2014 Key Seizure Signs and Symptoms
Symptoms Medical Terms automatic behaviors automatisms emotions or appearance of emotions emotions extension or flexion postures tonic flushing/sweating/piloerection autonomic jerking not rhythmic myoclonus jerking rhythmically clonus Language or thinking problems; de ja vu cognitive lid jerks eyelid myoclonia limp atonic numb/tingling, sounds, smells, tastes visions, sensations International vertigo League pausing, freezing, activity arrest behavior arrest, absence Against Thrashing/pedaling hyperkinetic Epilepsy (ILAE) Trunk flexion spasm What causes a seizure?
Primary causes (genetic)
Brain anomalies - structural
Channelopathies - electrical
A part of a genetic syndrome (structural and/or electrical)
Metabolic disturbance
Secondary causes (acquired)
Hypoxia
Hemorrhage
Stroke
Infection
Metabolic disturbance Define the phenotype for the patient
What is the epilepsy phenotype?
Semiology, age of onset
Is there evidence of syndromic features?
Dysmorphic features, other congenital anomalies
Are the symptoms static or progressive?
Metabolic abnormalities
Are there any focal findings based on history, EEG or neurological exam?
Brain mri findings Who should undergo genetic testing? Seizures + ….
Syndromic features Abnormal brain mri Dysmorphic features Migrational anomalies Neurocutaneous findings Polymicrogyria Overgrowth Congenital v. acquired Microcephaly White matter changes Neurodevelopmental Refractory epilepsy (on disorders multiple medications) Regression Type of epilepsy Motor delay Infantile spasms, atonic, myoclonic Language delay Family history epilepsy Autism spectrum Most Genetic Causes of Primary Epilepsy Remain Unknown
Michael S Hildebrand et al. J Med Genet 2013;50:271-279 Disease Mechanisms In Childhood Epileptic Encephalopathies
McTague A, et al. Lancet Neurol. 2016 Mar;15(3):304-16 Neurodevelopmental syndromes with Epilepsy Trisomy 21 Multiple types include infantile spasms Rett syndrome (MECP2, CDKL5, FOXG1) include infantile spasms Angelman syndrome (Missing maternal copy UBE3A; 15q11.2-q13 deletion, methylation, uniparental disomy) Multiple types including atonic, myoclonic Fragile X (CGG repeats FMR1) Multiple types including Focal, appear like benign centrotemporal spikes Neurocutaneous disorders with Epilepsy
Tuberous sclerosis
TSC1/TSC2
Risk tumors Sturge Weber
Mosaic GNAQ Incontinenti Pigmenti
X linked, IKBKG Primary Brain Structural Anomalies Signs and symptoms Abnormal head size Microcephaly Macrocephaly Abnormal tone Spasticity Asymmetric tone, hemiparesis Skin findings Seizure semiology Focal Atonic Generalized Primary Brain Structural Anomalies
Guerrini and Dobyns Lancet Neurology 2014 Primary Brain Structural Anomalies - Genetics
Lissencephaly
LIS1, ARX, DCX, RELN, Tubulinopathies
Megalencephaly
mTOR pathway
Polymicrogyria
Variable genetic and acquired
Bilateral perisylvian polymicrogyria - GPR56 Disease Mechanisms In Childhood Epileptic Encephalopathies
McTague A, et al. Lancet Neurol. 2016 Mar;15(3):304-16 Single gene epilepsy syndromes
Sporadic gene discovery
Family history driven
Helbig I, Heinzen EL, Mefford HC; ILAE Genetics Commission. Epilepsia. 2016 Jun;57(6):861-8. Primary Epilepsy Syndromes – Channelopathies - Dravet
Clinical Heterogeneity (same gene but different phenotype) Simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) Severe myoclonic epilepsy of infancy
Intractable epilepsy of childhood Allelic heterogeneity (same phenotype but different genes)
80% SCN1A pathogenic variants Pathophysiology Sodium channel Treatment implications
Avoid sodium blocking anti-seizure medications – oxcarbamazepine, phenytoin etc. Primary Epilepsy Syndromes – Channelopathies – KCNQ2 related
Clinical Heterogenetity
Benign familial epilepsy of infancy
Severe epileptic encephalopathy
Allelic heterogeneity
KCNQ2 and KCNQ3 pathogenic variants
Pathophysiology
Potassium channel
Treatment implications
Prefer sodium blocking anti-seizure medications – oxcarbamazepine, phenytoin etc. Primary Epilepsy Syndromes – Channelopathies – Landau Kleffner
Progressive loss of speech in a child with normal development Onset may start suddenly or slowly Age onset in children between 2 and 8 years old, most common average age of onset is 5 to 7 years of age Diagnose – Overnight Eeg with sleep ESES – electroclinical status epilepticus slow wave sleep Treatment steroids, high dose diazepam Genetics GRIN2A Polymorphic – gene + environment Disease Mechanisms In Childhood Epileptic Encephalopathies
McTague A, et al. Lancet Neurol. 2016 Mar;15(3):304-16 Epilepsy and Metabolic Conditions
Glucose transporter disorder GLUT-1 deficiency
Neonatal seizures, atonic and myoclonic
Neuronal ceroid lipofuscinosis disorders (NCL)
Progressive myoclonic epilepsy, retinal changes, degenerative
Inborn errors of metabolism Why is important to know the genetic cause of a patient’s epilepsy? Precision medicine in Epilepsy
Treatments of “cure” NCL – enzyme replacement therapy Dietary / metabolic GLUT1 – ketogenic diet Drug preference KCNQ2 – sodium channel blockers such as carbamazepine and oxcarbamazepine TSC1/TSC2 – vigabatrin for infantile spasms, mTOR inhibitors Everolimus Drug avoidance SCN1A – avoid sodium channel blockers Surveillance TSC1/TSC2 – increased risk for tumors in brain, kidney, lung and abdomen Genetic mechanisms
Epilepsia, Volume: 57, Issue: 6, Pages: 861-868, First published: 25 May 2016, DOI: (10.1111/epi.13381) What genetic test do I send?
Dunn et al. frontiers in Genetic Feb 2018 Vol 9 Article 20 Resources
Videos for seizure semiology
Infantile spasm - https://www.youtube.com/watch?v=r5VeRICWE7M
Tonic clonic - https://www.youtube.com/watch?v=FHrAQdPjINM
Atonic (head drops) https://www.youtube.com/watch?v=QPSWY0X3XYw
Websites
ILAE - https://www.ilae.org/
Genereviews – google gene or disorder and Genereviews
OMIM – use to look up a gene or genes related to a possible known disorder https://www.omim.org/